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Obstetrics & Gynecology:
doi: 10.1097/01.AOG.0000260871.87607.25
Original Research

Clinical and Pathologic Correlates in Surgical Stage II Endometrial Carcinoma

Cohn, David E. MD1,7; Woeste, Emily M. MD1; Cacchio, Stacey MD1; Zanagnolo, Vanna L. MD1; Havrilesky, Laura J. MD2; Mariani, Andrea MD3; Podratz, Karl C. MD, PhD3; Huh, Warner K. MD4; Whitworth, Jenny M. MD4; McMeekin, D Scott MD5; Powell, Matthew A. MD6; Boyd, Emily MD6; Phillips, Gary S. MAS7; Fowler, Jeffrey M. MD1

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From the 1Division of Gynecologic Oncology, Ohio State University College of Medicine, Columbus, Ohio; 2Division of Gynecologic Oncology, Duke University School of Medicine, Durham, North Carolina; 3Section of Gynecologic Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota; 4Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, Alabama; 5Division of Gynecologic Oncology, University of Oklahoma, Oklahoma City, Oklahoma; 6Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri; and 7Center for Biostatistics, Ohio State University College of Medicine, Columbus, Ohio.

Corresponding author: Dr. David E. Cohn, 320 West 10th Avenue, M-210 Starling Loving Hall, Columbus, OH 43210; e-mail: David.Cohn@osumc.edu.

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Abstract

OBJECTIVE: To identify the surgical, pathologic, and therapeutic factors that influence outcome in patients with surgical stage II endometrial adenocarcinoma.

METHODS: All patients with comprehensively staged stage II endometrial adenocarcinoma were identified. Data regarding preoperative, surgical, pathologic, adjuvant therapy, and outcomes were collected. Factors were compared with the χ2 test, and survival curves were generated and compared with the log rank test.

RESULTS: Of 162 patients with surgical stage II endometrial cancer, the median age was 65 years, and the median body mass index was 31.2 kg/m2. An extrafascial hysterectomy was performed in 75% of cases, whereas 25% of patients underwent radical hysterectomy. At least 10 nodes were recovered in more than 90% of cases. Stage IIA disease was present in 52% of cases, whereas stage IIB accounted for the remaining 48%. After staging, 48% of patients had adjuvant radiation therapy (16% with brachytherapy alone). The remainder received no adjuvant therapy. At a median follow-up of 26 months, 17% experienced disease recurrence. Five-year overall survival rate was 88% and disease-free survival rate was 81%. A significantly better 5-year disease-free survival rate was seen in patients undergoing radical hysterectomy compared with extrafascial hysterectomy (94% compared with 76%, P=.05). Adjuvant radiation did not lead to improved survival.

CONCLUSION: In this large series of surgical stage II endometrial cancer cases, improved survival was noted relative to historical controls and in particular with radical compared with extrafascial hysterectomy.

LEVEL OF EVIDENCE: II

Endometrial cancer is the most frequently occurring gynecologic cancer in the United States.1 In general, prognosis is favorable in that most patients are diagnosed when disease is confined to the uterine corpus (surgical stage I), and the 5-year survival rate exceeds 90%. However, a subset of patients has a poor outcome, including those with high-risk histology, extrauterine disease (surgical stage III and IV), and involvement of the uterine cervix (surgical stage II). Previous studies suggest that involvement of the cervix by endometrial adenocarcinoma occurs in approximately 10% of cases and carries a 5-year survival rate of approximately 70%.2 As such, many patients with stage II disease are treated using methods including extrafascial hysterectomy before or after radiation therapy or primary radical surgery.3 To date, there have been no prospective studies comparing these treatment strategies given the relative rarity of surgical stage II endometrial cancer. Furthermore, many previous retrospective reports did not include patients with comprehensive surgical staging, thereby clouding the results related to treatment of this disease. As such, we set out to identify a large series of comprehensively surgically staged patients with stage II endometrial adenocarcinoma in an effort to identify preoperative, operative, pathologic, and therapeutic factors that predict outcome in this disease.

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MATERIALS AND METHODS

After review at the institutional review boards of participating sites, cases of endometrial adenocarcinoma were identified from respective databases from six university-based gynecologic oncology practices (The Ohio State University, Duke University, Mayo Clinic, University of Alabama at Birmingham, University of Oklahoma, and Washington University). Inclusion criteria included comprehensive surgical staging (including hysterectomy, adnexectomy, pelvic and para-aortic lymphadenectomy), with disease metastatic only to the cervix. Cases reviewed spanned from 1982 to 2004, with 90% of cases taken being treated after 1990. Data were collected regarding patient demographics, surgical treatment, surgical pathology, postoperative adjuvant treatment, and patient outcome. For statistical comparisons, body mass index (BMI) was divided into three categories (ideal body weight, less than 30 kg/m2; obese, 30–40 kg/m2; morbidly obese, more than 40 kg/m.2 Lymph node yield was arbitrarily defined as being adequate when the total lymph node count was 10 or more, including a pelvic lymph node count of six or more, and an aortic lymph node yield of four or more. Radiation therapy was separated into groups of teletherapy (with or without brachytherapy) and brachytherapy alone. Survival time was calculated from the date of primary surgery to the date of last contact or death. Univariable analysis was performed using the χ2 or Fisher exact test. Individual factors were also included in a Cox proportional hazards model using univariable and multivariable regression. Survival was estimated with the Kaplan-Meier product-limit method and compared with the log rank test.

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RESULTS

From six academic gynecologic oncology practices, 162 patients with surgical stage II endometrial adenocarcinoma were identified and serve as the basis of this report. The median age of patients was 65 years (range 34–89 years) at the time of surgery, with 65% of patients being older than 60 years. The median BMI was 31.2 kg/m2 (range 17.7–62.5), with 48% of patients classified as obese and 46% morbidly obese (Table 1).

Table 1
Table 1
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Primary surgical management included an extrafascial hysterectomy in 75% of cases and a radical (type II or III hysterectomy) in the remaining 25% of cases. Stage IIA disease was diagnosed in 52% of cases, whereas stage IIB disease was diagnosed in the remaining 48%. The majority of endometrial cancer specimens demonstrated inner-half myometrial invasion from a grade 2 adenocarcinoma. Lymphvascular space involvement was present in 27% of cases. More than 10 lymph nodes were removed in 90% of cases. An adequate lymphadenectomy (with at least six pelvic and four aortic lymph nodes) was performed in 71% of cases. The median pelvic lymph node count was 16, and the median para-aortic lymph node count was five (Table 2).

Table 2
Table 2
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Postoperatively, 48% of patients were treated with adjuvant radiation therapy: 15% received teletherapy and brachytherapy, 17% received teletherapy only, and 16% received brachytherapy only after surgery for their stage II endometrial cancer. The remaining 48% of patients did not receive adjuvant therapy after surgery. Of the 121 patients treated with extrafascial hysterectomy, 30 (25%) were treated with teletherapy (with or without brachytherapy), whereas only 5% who underwent radical hysterectomy received adjuvant teletherapy.

At a median follow-up of 26 months (range 1–186 months), 27 patients (17%) had experienced disease recurrence. Five-year overall survival rate was 88% (89% for stage IIA and 85% for stage IIB), and the 5-year disease-free survival rate for the entire group was 81% (Table 3, Fig. 1). Most epidemiologic and pathologic factors evaluated failed to predict patient outcome (including age, BMI, tumor grade, depth of myometrial invasion, lymph node counts, and the use of adjuvant radiation, Table 4). However, patients managed with radical hysterectomy had improved disease-free survival compared with those treated with extrafascial hysterectomy (5-year survival rate 94% compared with 76%, P=.05, Fig. 2). In those treated with extrafascial hysterectomy, patients treated with adjuvant teletherapy had a 5-year disease-free survival rate of 84% compared with 80% in those who did not receive adjuvant teletherapy (P=.7, Fig. 3). Interestingly, the 5-year overall survival in women with a BMI less than 30 kg/m2 was significantly better than in women with a BMI more than 40 kg/m2 (83% compared with 54%, P<.007, data not shown). However, patients of ideal body weight were not more likely to undergo radical hysterectomy compared with obese women (Table 1). No factors were shown to significantly predict recurrence in a multivariable model; specifically, radiation therapy was not shown to improve survival in this model regardless of the type of hysterectomy performed (data not shown).

Table 3
Table 3
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Fig. 1
Fig. 1
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Table 4
Table 4
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Fig. 2
Fig. 2
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Fig. 3
Fig. 3
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DISCUSSION

In this large series of contemporarily treated patients with surgical stage II endometrial cancer, we demonstrate a more favorable survival than that reported in historical cohorts. Furthermore, it seems that primary radical hysterectomy provides a survival advantage compared with extrafascial hysterectomy, with or without adjuvant radiation therapy. The reporting of many different management strategies in different patient populations has complicated interpretation of previous studies of stage II endometrial cancer. Specifically, the majority of prior retrospective studies reported patients who did not undergo comprehensive surgical staging with pelvic and para-aortic lymphadenectomy. Furthermore, primary management of patients with a preoperative diagnosis of clinical stage II endometrial cancer varies from preoperative brachytherapy followed by extrafascial hysterectomy or primary radical hysterectomy with adjuvant radiation reserved for patients with risk factors predicting a high risk for recurrence after surgery (such as disease in the parametrium or a positive vaginal margin). Patients found to have occult stage II disease after extrafascial hysterectomy have been managed by various methods, including brachytherapy alone, teletherapy (with or without brachytherapy), or no adjuvant therapy. Given the variations in the surgical management and use of adjuvant therapy of patients with stage II endometrial cancer, we believed that further study of this population was necessary to attempt to define appropriate options or management of this disease.

Importantly, the overall (88%) and disease-free (81%) survival in our entire group of patients with comprehensively staged, stage II endometrial cancer is superior than that reported in previous reports. In the most recent Annual Report on the Results of Treatment in Gynecologic Cancer (FIGO, 2003),4 reporting on patients managed from 1996–1998, the overall 5-year survival rate for surgical stage II endometrial cancer was 75%, compared with 46% in the 67 patients reported with clinical stage II endometrial cancer during the reporting period. In this report, it is interesting to note that 97% of patients (963 of 984) were reported to have been “surgically staged.” The reasons for the improved survival seen in our report are uncertain. Given the high rate of what was arbitrarily defined as adequate lymphadenectomy, it could be hypothesized that stage migration (identification of nodal metastasis and assignment of these patients to stage IIIC) or a therapeutic effect of lymphadenectomy5 could account for the improved survival seen in our patients. Alternatively, because the radicality of the primary surgical resection was not always reported in previous studies, our improved survival may be related to the use of radical hysterectomy for the management of stage II endometrial cancer.

In our study, we demonstrate that patients undergoing a type II or III radical hysterectomy for management of stage II endometrial cancer have an improved survival rate compared with patients undergoing extrafascial hysterectomy. Although there has never been a prospective study comparing extrafascial to radical hysterectomy for patients with positive endocervical curettage or clinical expansion of the cervix from endometrial cancer, retrospective studies have suggested that primary radical surgery improves survival in women with this disease.6,7 Mariani et al6 report that in patients undergoing radical hysterectomy and pelvic lymphadenectomy, 5-year disease-free survival rate was 88% in the 57 patients with surgical stage II endometrial cancer. In the 68 patients reported by Sartori et al7 undergoing radical hysterectomy and pelvic lymphadenectomy, the 5-year survival rate was 94%, compared with 79% in the 135 patients undergoing extrafascial hysterectomy. Cornelison et al8 used 1998 SEER data to determine that the 5-year overall survival rate in 377 patients with surgical stage II endometrial cancer undergoing radical hysterectomy was 93%, compared with 84% in those undergoing extrafascial hysterectomy. In our study, very similar results were noted, with a 5-year survival rate of 94% in those undergoing radical hysterectomy, compared with 76% for those undergoing extrafascial hysterectomy. From these data, it would be tempting to recommend that all patients undergo endocervical curettage for surgical treatment planning in a patient with newly diagnosed endometrial cancer, with radical hysterectomy performed for all patients with clinical stage II disease. However, endocervical curettage has been reported to have only a moderate sensitivity in detecting histologic involvement of the cervix at the time of hysterectomy, and correlation between clinical and surgical stage II endometrial cancer is often inaccurate.9 As such, subjecting patients to the potentially increased morbidity of radical pelvic surgery without clear evidence of its necessity would seem unwise. It is extremely unlikely that a prospective evaluation of radical compared with extrafascial hysterectomy for the management of clinical stage II endometrial cancer will ever be undertaken; as such, the retrospective data must serve as the basis by which surgical management of patients with clinical stage II endometrial cancer is determined. In this study, it is important to recognize that the primary surgical management was at the discretion of the treating physician and therefore subject to significant personal or institutional selection bias. However, many surgeons would select to perform a radical hysterectomy in the presence of clinical expansion of the cervix or pathologic extension to the endocervix. Unfortunately, the status of the Papanicolaou test and or the endocervical curettage could not be reliably ascertained in the patients reported in this study.

It is often hypothesized that in patients with surgical stage II disease, equivalent outcomes are noted between patients undergoing radical hysterectomy without adjuvant radiation and those undergoing extrafascial hysterectomy with adjuvant radiation.10 However, in most studies describing the effect of radical surgery on survival in comprehensively staged, stage II endometrial cancer, there are no data suggesting that adjuvant teletherapy after extrafascial hysterectomy leads to survival equivalent to patients undergoing radical hysterectomy.11 In our study, we do not show any survival advantage to the use of adjuvant radiation therapy in the univariable or multivariable model. It must be acknowledged, however, that this analysis may lack the power to determine a difference, given the small number of patients in each group being compared (extrafascial hysterectomy and adjuvant teletherapy compared with no adjuvant radiation, for example). Given the length of time needed to collect the 162 cases reported in this study, it is unlikely that a sample size large enough to detect a difference will be reported.

Many studies have previously reported excellent outcomes after extrafascial hysterectomy and lymphadenectomy for surgical stage II endometrial cancer without teletherapy.12 As such, studies suggesting that radiation overcomes the worse survival reported with extrafascial hysterectomy must be interpreted with caution. Interestingly, we have observed that in patients with morbid obesity, 5-year survival was significantly worse than in obese patients (54%) and those with ideal body weight (83%, P<.007). The reasons for the worse survival in the heaviest patients are uncertain and deserve further study; however, the avoidance of radical surgery in obese women with stage II endometrial cancer does not seem to be responsible for this difference, because the rate of radical surgery was not significantly different when stratified by BMI.

In the only prospective study of the role of radiation therapy in patients with occult stage II endometrial cancer (Gynecologic Oncology Group Study 9913), patients did require surgical staging for entry; however, only 37 patients with stage II disease were investigated, half of whom received whole pelvic radiotherapy after surgical staging (including at least extrafascial hysterectomy pelvic and aortic lymphadenectomy), whereas the other received no adjuvant therapy. Given the small number of patients in these groups, survival for patients with stage II endometrial cancer was not reported separately. Data from other sources, such as the American College of Surgeons National Cancer Data Base, have also failed to demonstrate a survival advantage to the use of adjuvant radiation after comprehensive staging in surgical stage II endometrial cancer.11

In summary, we demonstrate excellent comparative survival in patients with surgical stage II endometrial cancer, and show that radical hysterectomy affords improved survival compared with extrafascial hysterectomy. Despite the relatively large sample size reported herein, the role of adjuvant radiation after comprehensive surgical staging of a stage II endometrial cancer remains unproven.

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REFERENCES

1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer Statistics, 2006. CA Cancer J Clin 2006;56:106–30.

2. Trimble EL, Jones HW 3rd. Management of stage II endometrial adenocarcinoma. Obstet Gynecol 1988;71:323–6.

3. Mannel RS, Berman ML, Walker JL, Manetta A, DiSaia PJ. Management of endometrial cancer with suspected cervical involvement. Obstet Gynecol 1990;75:1016–22.

4. Creasman WT, Odicino F, Maisonneuve P, Beller U, Benedet JL, Heintz AP, et al. Carcinoma of the corpus uteri. Int J Gynecol Obstet 2003;83 suppl:79–118.

5. Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin F 3rd, et al. Adenocarcinoma of the endometrium: survival of patients with and without pelvic lymph node sampling. Gynecol Oncol 1995;56:29–33.

6. Mariani A, Webb MJ, Keeney GL, Calori G, Podratz KC. Role of wide/radical hysterectomy and pelvic lymph node dissection in endometrial cancer with cervical involvement. Gynecol Oncol 2001;83:72–80.

7. Sartori E, Gadducci A, Landoni F, Lissoni A, Maggino T, Zola P, et al. Clinical behavior of 203 stage II endometrial cancer cases: the impact of primary surgical approach and of adjuvant radiation therapy. Int J Gynecol Cancer 2001;11:430–7.

8. Cornelison TL, Trimble EL, Kosary CL. SEER data, corpus uteri cancer: treatment trends versus survival for FIGO stage II, 1988–1994. Gynecol Oncol 1999;74:350–5.

9. Creasman WT, DeGeest K, Disaia PJ, Zaino RJ. Significance of true surgical pathologic staging: a Gynecologic Oncology Group Study. Am J Obstet Gynecol 1999;181:31–4.

10. Ayhan A, Taskiran C, Celik C, Yuce K. The long-term survival of women with surgical stage II endometrioid type endometrial cancer. Gynecol Oncol 2004;93:9–13.

11. Straughn JM Jr, Numnum TM, Kilgore LC, Partridge EE, Phillips JL, Markman M, et al. The use of adjuvant radiation therapy in patients with intermediate-risk Stages IC and II uterine corpus cancer: A patient care evaluation study from the American College of Surgeons National Cancer Data Base. Gynecol Oncol 2005;99:530–5.

12. Horowitz NS, Peters WA 3rd, Smith MR, Drescher CW, Atwood M, Mate TP. Adjuvant high dose rate vaginal brachytherapy as treatment of stage I and II endometrial cancer. Obstet Gynecol 2002;99:235–40.

13. Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92:744–51.

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